Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy
Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy
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DOI：
10.1016/s0896-6273(02)00834-6
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发表时间：
2002-08-29
期刊：
影响因子：
16.2
通讯作者：
Sobue, G
中科院分区：
文献类型：
--
作者：
Katsuno, M;Adachi, H;Sobue, G
脊髓和球性肌萎缩症（SBMA）是一种由雄激素受体（AR）基因中CAG重复扩增引起的多谷氨酰胺疾病。我们构建了一个携带含有97个cag的全长AR的转基因小鼠模型。5个系中有3个表现出进行性肌肉萎缩和虚弱，以及弥散性核染色和包含突变AR的核内含物。这些表型在雄性转基因小鼠中明显存在，并在去势后显著恢复。雌性转基因小鼠仅表现出少数明显恶化的表现。睾丸激素引起的AR突变体核易位导致了性别和激素干预的表型差异。这些结果表明激素干预对SBMA的治疗潜力。
Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine disease caused by the expansion of a CAG repeat in the androgen receptor (AR) gene. We generated a transgenic mouse model carrying a full-length AR containing 97 CAGs. Three of the five lines showed progressive muscular atrophy and weakness as well as diffuse nuclear staining and nuclear inclusions consisting of the mutant AR. These phenotypes were markedly pronounced in male transgenic mice, and dramatically rescued by castration. Female transgenic mice showed only a few manifestations that markedly deteriorated with testosterone administration. Nuclear translocation of the mutant AR by testosterone contributed to the phenotypic difference with gender and the effects of hormonal interventions. These results suggest the therapeutic potential of hormonal intervention for SBMA.